Editing Pediatrics: Renal and Adrenal Oncology (section)

== Neuroblastoma ==

=== Background ===
* '''Arises from cells of the neural crest''' that form the adrenal medulla and sympathetic ganglia
* '''Tumors may occur anywhere along the sympathetic chain''' '''within the'''
*#'''Neck'''
*#'''Thorax'''
*#'''Retroperitoneum (including adrenal gland)'''
*#*75% originate in the retroperitoneum of which 50% originate in the adrenal and 25% in the paravertebral ganglia
*#'''Pelvis'''

=== Epidemiology ===
* '''<span style="color:#ff0000">Most common malignant tumour in infants''' (child age < 1)§
* '''Most common extracranial solid tumor of childhood'''
** In children, leukemia most common, followed by brain tumours
* '''<span style="color:#ff0000">Median age at diagnosis of 19 months (vs. Wilm’s 3.5 years)'''
* '''Screening discovers tumours with an improved prognosis, but does not reduce occurrence of neuroblastoma in older children and its subsequent mortality'''

=== Genetics ===
* PHOX2B and ALK as hereditary predisposition genes
* '''≥20% of patients with familial neuroblastoma have bilateral adrenal or multifocal primary tumors; bilateral adrenal or multifocal primary tumors are rare in spontaneous cases'''

=== Natural History ===

* '''Tumors can either (3)'''
** '''Undergo spontaneous regression''' 
** '''Differentiate to benign neoplasms''' 
** '''Exhibit extremely malignant behavior'''

=== Pathology ===
* '''Shimada classification'''
** '''An age-linked histopathologic classification'''
** '''An important aspect is determining whether the tumor is stroma poor or stroma rich.'''
*** Subgroups of stroma-rich tumors (3):
***# Nodular
***# Intermixed
***# Well differentiated
**** Ganglioneuroma is a stroma-rich tumour
*** '''Subgroups of stroma-poor tumors (2)'''
***# '''Favorable'''
***# '''Unfavorable'''
**** '''Based on (3):'''
****# '''Age at diagnosis'''
****# '''Degree of histologic maturation'''
****# '''Mitotic rate'''
***** These histologic patterns are independently predictive of outcome.
****** '''Stroma-poor tumors with unfavorable histopathologic features have a very poor prognosis (< 10% survival)'''
* '''In situ neuroblastoma'''
** '''Small nodules of neuroblastoma cells found incidentally within the adrenal gland'''
** '''Histologically indistinguishable from neuroblastoma'''
** '''These small tumors regress spontaneously in most cases'''

=== Diagnosis and Evaluation ===

==== History and Physical Exam ====
* '''Clinical manifestations vary widely'''
** '''<span style="color:#ff0000">Most children have abdominal pain or a palpable mass'''
*** '''Most primary tumors arise within the abdomen (65%)'''
**** Physical examination often reveals a fixed, hard abdominal mass
*** '''Pelvic neuroblastoma arising from the organ of Zuckerkandl account for 4% of tumors.'''
**** Extrinsic compression of the bowel and bladder can produce symptoms of urinary retention and constipation.
** '''<span style="color:#ff0000">Other are identified because of manifestations of metastatic disease, including bone or joint pain and periorbital ecchymosis.'''
*** '''Metastases are present in 70% of patients with neuroblastoma at diagnosis'''
** '''<span style="color:#ff0000">Symptoms produced by catecholamines'''
*** '''<span style="color:#ff0000">Release may mimic those seen in pheochromocytoma: paroxysmal hypertension, palpitations, flushing, and headache'''
*** '''Secretion of vasoactive intestinal peptide (VIP) can produce severe watery diarrhea and hypokalemia'''

==== Labs ====
* '''<span style="color:#ff0000">Urinary metabolites of catecholamines, vanillylmandelic acid (VMA) and homovanillic acid (HVA)'''
**'''Increased levels are found in 90-95% of patients'''
*** These metabolites can be monitored to detect tumor relapse and response to therapy
* '''CBC'''
**'''Anemia''' '''is found with widespread bone marrow involvement'''
[[File:Neuroblastoma 103.jpg|alt=Axial CT scan of Neuroblastoma|thumb|500x500px|Axial CT scan of Neuroblastoma. Source: [[commons:File:Neuroblastoma_103.jpg|Wikipedia]]]]

==== Imaging ====
* '''<span style="color:#ff0000">CT or MRI'''
** '''Provide more information about the local extent of the primary tumors and vascular involvement'''
** '''Advantages of MRI over CT'''
*** '''Evaluating intraspinal tumor extension, which is not uncommon in paravertebral lesions'''
*** Demonstrating the relationship between the major vessels and the tumor
** '''<span style="color:#ff0000">CT findings'''
**# '''<span style="color:#ff0000">Crossing midline'''
**# '''<span style="color:#ff0000">Vascular encasement'''
**# '''<span style="color:#ff0000">Intra-tumoral stippled calcifications'''
**#* '''Note that egg-shell calcifications are found in adrenal hemorrhage, which may also present in the neonate as an abdominal mass'''
*** '''<span style="color:#ff0000">These imaging characteristics are absent in Wilms tumor'''
*'''Plain radiographs'''
** May demonstrate a '''calcified abdominal or posterior mediastinal mass'''
* '''Radionuclide bone scan and metaiodobenzylguanidine (MIBG) scans for can be used staging'''

==== Other ====
* '''Bone marrow biopsies'''
**'''Marrow biopsies add substantially to the detection of marrow involvement by tumor,''' compared with marrow aspirates alone.
*** '''2 marrow aspirates and 2 biopsies are recommended'''

=== Staging ===
{| class="wikitable"
|'''Stage'''
|'''Description'''
|-
|'''1'''
|
* Localized tumor
* Complete gross excision
* Ipsilateral lymph nodes involvement negative under microscopic examination
|-
|'''2A'''
|
* Localized tumor
* '''Incomplete gross resection'''
* Ipsilateral lymph nodes involvement negative under microscopic examination
|-
|'''2B'''
|
* Localized tumor
* Complete or incomplete gross resection
* '''Ipsilateral lymph nodes involvement positive under microscopic examination'''
* Enlarged contralateral lymph nodes but with negative involvement under microscopic examination
|-
|'''3'''
|
* '''Localized unilateral tumor with contralateral lymph nodes involvement positive under microscopic examination'''

<center>'''or'''</center>

* '''<span style="color:#ff0000">Unresectable unilateral tumor</span> infiltrating across the midline''' with positive or negative regional lymph node involvement

<center>'''or'''</center>

* Unresectable midline tumor with bilateral infiltration or lymph node involvement
|-
|'''4'''
|
* '''<span style="color:#ff0000">Metastasis of the tumor to distant lymph nodes'''
* '''<span style="color:#ff0000">Metastasis of the tumor to liver, skin, organs (except as defined by Stage 4S)'''
|-
|'''4S'''
|
* '''Limited to infants <1 year of age'''
* '''Localized primary tumor (as defined for stage 1, 2A, or 2B)'''
* '''Metastasis of the tumor limited to skin, liver and/or bone marrow'''
* '''Bone marrow involvement in stage 4S should be minimal''' (<10% of total nucleated cells identified as malignant on bone marrow biopsy)
|}

=== Prognosis ===
* '''Adverse prognostic factors (7): SSANDS-1'''
** '''Clinical Variables'''
**# '''Stage''': powerful independent prognostic indicator
**# '''Site of origin: adrenal primary'''
**# '''Age > 1;''' may be attributed to more unfavorable biologic parameters in tumors diagnosed at this age
** '''Biologic Variables'''
**# '''Amplification of the MYCN oncogene''' (20-25% of primary tumors)
**#* Present in 40% of patients with advanced-stage disease but in only 5-10% of children with low-stage disease
**#* Associated with rapid tumor progression and poor outcome
**# '''DNA index:''' normal or tetraploid DNA number when compared with tumors that have '''aneuploidy of the tumor DNA'''
**# '''Shimada histopathology (stroma rich vs. poor, mitotic rate, differentiation)'''
**# '''Deletion of the short arm of chromosome 1'''p

=== Management ===
* Primary treatment modalities:
*# Surgery
*# Chemotherapy
*# Radiation therapy
** The role of each depends on tumor stage, age, and biologic prognostic factors.
* '''<span style="color:#ff0000">Infants < 6 months with localized small adrenal masses can be managed with serial observation.'''
** '''Frequently associated with spontaneous regression'''
** '''Surgical resection can be avoided in 80% of such patients'''
* '''<span style="color:#ff0000">Low-Risk Disease (Stages 1 and 2): surgery (adrenalectomy)''' 
** Disease-free survival with surgical excision (adrenalectomy) alone in children with stage 1 neuroblastoma: > 90%
** '''<span style="color:#ff0000">Radical resection resulting in removal of normal organs, particularly the kidney, is not justified'''
***'''In stage 3 disease, or in stage 2 with extensive tumor around the kidney and renal vessels, preoperative treatment with chemotherapy significantly decreases the risk of nephrectomy as a result of resection of the tumor.'''
** Radiation of the local tumor bed has been advocated for treatment of residual disease in stage 2
* '''<span style="color:#ff0000">Intermediate- and High-Risk Disease (Stages 3 and 4): neoadjuvant chemotherapy followed by surgery'''
** '''Usually the safest approach for advanced tumors is to defer resection until after initial chemotherapy'''
** Neoadjuvant chemotherapy, given the efficacy of modern agents, is very successful in reducing the size of primary tumors
** There is debate regarding the extent of surgical resection that is required for stage 3 lesions
** Conflicting evidence regarding the benefit of extensive resection in children with stage 4 disease  
** '''<span style="color:#ff0000">Surgery usually is performed 13-18 weeks after initiation of chemotherapy, allowing 3-4 courses of treatment'''
** Infants age <1 year with extensive local disease or stage 4 disease comprise a special subset of patients. They have historically fared much better than children older than 1 year of age with comparable disease, but not as well as infants with stage 4S disease. It is now recognized that the biologic markers can be used to identify which infants have high-risk disease and require intensive therapy and which have intermediate-risk disease requiring less intensive therapy.
* '''Stage 4S'''
** The vast majority of these infants with '''stage 4S disease''' have tumors with entirely favorable markers, explaining their favorable behavior. However, a small fraction have adverse markers, and it is these children who have progressive disease that often is fatal.
** '''Resection of the primary is not mandatory'''
*'''Patients with extensive metastatic disease and MYCN amplification represent a high-risk group. These patients should be considered for a more aggressive treatment with multimodal therapy''', according to the risk group classification.
**Those with favorable biologic markers and no symptoms can be followed with supportive care and limited chemotherapy. 
**Intensive chemotherapy is reserved for those with adverse markers, although these infants do poorly even with therapy.
* '''Indications for adjuvant chemotherapy'''
** '''MYCN amplification and unfavorable histology'''
** '''Disease recurrence'''
*Chemotherapy
** A variety of multiagent regimens have been developed to treat high-risk patients with neuroblastoma
* '''Radiotherapy'''
** '''Radiotherapy is effective for local control in neuroblastoma,''' and risk of local relapse can be correlated with the biologic markers. '''Although irradiation has not provided a benefit in low-stage tumors, it has increased local control in children with advanced stage 4 or bulky stage 3 tumors'''